rs11542040

chr19-44908600-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000041.4(APOE):c.304C>A(p.Pro102Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_000041.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.304C>A	p.Pro102Thr	missense_variant	4/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.304C>A	p.Pro102Thr	missense_variant	4/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.304C>A	p.Pro102Thr	missense_variant	3/3	1
APOE	ENST00000434152.5	c.382C>A	p.Pro128Thr	missense_variant	4/4	2
APOE	ENST00000446996.5	c.304C>A	p.Pro102Thr	missense_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460616 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.76	D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.7	D;D;.;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.62
MutPred		0.58		Gain of phosphorylation at P102 (P = 0.0241);Gain of phosphorylation at P102 (P = 0.0241);.;Gain of phosphorylation at P102 (P = 0.0241);
MVP		0.99
MPC		1.7
ClinPred		0.91	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.63
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11542040; hg19: chr19-45411857;